HMGN5 escorts oncogenic STAT3 signaling by regulating chromatin landscape in tumorigenesis of breast cancer
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ABSTRACT:
PROVIDER: PRJNA796499 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17574923_1.fastq.gz | Fastqsanger.gz | |||
| SRR17574923_2.fastq.gz | Fastqsanger.gz | |||
| SRR17574924_1.fastq.gz | Fastqsanger.gz | |||
| SRR17574924_2.fastq.gz | Fastqsanger.gz | |||
| SRR17574925.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic alterations are widely linked with carcinogenesis, therefore becoming emerging therapeutic targets in the treatment of cancers, including breast cancer. HMGNs are nucleosome binding proteins, which regulate chromatin structures in a cell type- and disease-specific manner. However, the roles of HMGNs in the tumorigenesis of breast cancer are less known. In this study, we report that HMGNs are highly expressed in 3D-cultured breast cancer cells. HMGN5, a member of HMGNs, controls the proliferation, invasion and metastasis of breast cancer cells in vitro and in vivo. Clinically, HMGN5 is an unfavorable prognostic marker in patients. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape oncogenic chromatin landscape and transcriptional program. Lastly, we provide evidence that interference of HMGN5 by nanoparticle-packaged siRNA is potentially an effective approach in breast cancer treatment. Taken together, our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic target in STAT3-hyperactive breast cancer.
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Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
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Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance
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Project description:In most metazoan nuclei, heterochromatin is located at the nuclear periphery in contact with the nuclear lamina, which provides mechanical stability to the nucleus. We show that in cultured cells, chromatin de-compaction by the nucleosome binding protein HMGN5 decreases the sturdiness, elasticity, and rigidity of the nucleus. Mice overexpressing HMGN5, either globally or only in the heart, are normal at birth but develop hypertrophic heart with large cardiomyoctyes, deformed nuclei and disrupted lamina, and die of cardiac malfunction. Chromatin de-compaction is seen in cardiomyocytes of newborn mice but misshaped nuclei with disrupted lamina are seen only in adult cardiomyocytes, suggesting that loss of heterochromatin diminishes the ability of the nucleus to withstand the mechanical forces of the contracting heart. Thus, heterochromatin enhances the ability of the nuclear lamina to maintain the sturdiness and shape of the eukaryotic nucleus; a structural role for chromatin that is distinct from its genetic functions. The full length mouse Hmgn5 cDNA, containing the entire 5’ UTR and FLAG tag on the 3’ end was amplified by PCR and inserted between BglII and XhoI sites of the pCALL vector (Novak et al., 2000). This vector contains a floxed LacZ cDNA driven by the CAG (a hybrid CMV enhancer and chicken beta–actin) promoter which is highly active in early mouse embryos. The vector was linearized by NotI digestion and injected into fertilized oocytes of C57BL/6 mice. Total embryonic excision of LacZ sequence was done by breeding floxed HMGN5-TG mice with SoxCre mice (Hayashi et al., 2002). Heart-specific excision was performed by breeding floxed HMGN5-TG mice with alphaMHC-cre mice (Oka et al., 2006).Total RNA from the left ventricle of newborn and adult Hmgn5-hTG mice which overexpress HMGN5 only in the heart as well as control mice was collected from biological triplicates (duplicates, in the case of newborn wild-type mice) and analyzed by Affymetrix expression arrays.
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Project description:HMGN5 is a member of the HMGN family that de-compacts chromatin and regulates gene expression. Chromatin-associated RNAs are known to play a major role in controlling gene expression and chromatin architecture. We recently showed that RNA is required to open chromatin structure in Drosophila. A potential involvement of RNA in the HMGN5-dependent opening of chromatin has not been studied so far. Here we revealed that HMGN5 has a novel and specific RNA binding activity, which is extended to the HMGN family. HMGN5 is associated preferentially with active regulatory regions and binds co-transcriptionally to the nascent RNA. Additionally, we showed that HMGN5 co-localizes and interacts with CTCF, which suggests a cooperative role of both proteins in organizing higher order structures of chromatin. We showed that HMGN5 forms mutually exclusive complexes with chromatin and RNA in vitro, altogether suggesting a dual role for HMGN5 in gene regulation, switching from nucleosome to RNA binding during gene activation.
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Project description:HMGN5 is a member of the HMGN family that de-compacts chromatin and regulates gene expression. Chromatin-associated RNAs are known to play a major role in controlling gene expression and chromatin architecture. We recently showed that RNA is required to open chromatin structure in Drosophila. A potential involvement of RNA in the HMGN5-dependent opening of chromatin has not been studied so far. Here we revealed that HMGN5 has a novel and specific RNA binding activity, which is extended to the HMGN family. HMGN5 is associated preferentially with active regulatory regions and binds co-transcriptionally to the nascent RNA. Additionally, we showed that HMGN5 co-localizes and interacts with CTCF, which suggests a cooperative role of both proteins in organizing higher order structures of chromatin. We showed that HMGN5 forms mutually exclusive complexes with chromatin and RNA in vitro, altogether suggesting a dual role for HMGN5 in gene regulation, switching from nucleosome to RNA binding during gene activation.
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Project description:HMGN5 is a member of the HMGN family that de-compacts chromatin and regulates gene expression. Chromatin-associated RNAs are known to play a major role in controlling gene expression and chromatin architecture. We recently showed that RNA is required to open chromatin structure in Drosophila. A potential involvement of RNA in the HMGN5-dependent opening of chromatin has not been studied so far. Here we revealed that HMGN5 has a novel and specific RNA binding activity, which is extended to the HMGN family. HMGN5 is associated preferentially with active regulatory regions and binds co-transcriptionally to the nascent RNA. Additionally, we showed that HMGN5 co-localizes and interacts with CTCF, which suggests a cooperative role of both proteins in organizing higher order structures of chromatin. We showed that HMGN5 forms mutually exclusive complexes with chromatin and RNA in vitro, altogether suggesting a dual role for HMGN5 in gene regulation, switching from nucleosome to RNA binding during gene activation.
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